One of the major challenges in developing treatments for type 1 diabetes (T1D) is understanding the mechanisms behind how the immune system mistakenly destroys beta cells — the cells that make insulin — to cause T1D.
A paper published in the Feb. 13, 2019, edition of the journal Nature explores new ways of replacing beta cells after too many of them have been killed by the immune system — and in a way that makes them less attractive to the immune system’s urge to eradicate them.
“Different sources of new beta cells exist, and many of these are also present in patients with T1D,” Roep explained. “We found that human pancreatic alpha cells can be engineered to be turned into insulin producers, which in turn reversed diabetes, curing the disease in mice.”
Furthermore, these pseudobeta cells are less likely to provoke an immune response than the original beta cells, meaning they may be able to live within the same immune system that eliminated the beta cells that came before them. If true, this would help remove a considerable hurdle in islet replacement therapy. In addition, the alpha cells made to produce insulin in the study seem less stressed, another major problem that can lead to the depletion of beta cells in patients with T1D.
According to Roep, these findings mean that doctors might be able to forge new sources of insulin without the need for organ donors one day, including performing autologous transplants, meaning they would use cells from a patient’s own body that have been treated to be resistant to immune attack. These methods would hopefully reduce the need for the immune-suppression drugs necessary for current islet transplant therapies. However, it is important to note that the Nature study provides conceptual evidence that human islet cells could be engineered to treat diabetes; further testing is needed to see if the findings will translate in human subjects.
“Perhaps with innovative technologies, we will be able to turn some of the alpha cells into beta cells in the pancreas,” Roep said.
New Perspectives on an Old Foe
The Nature study comes on the heels of two other papers co-authored by Roep published in The Lancet Diabetes & Endocrinology. The two-paper series covers the results of current and recent clinical trials for immunotherapies to deal with the immune attack on beta cells — the other end of the spectrum from the Nature study — and the challenges faced, as well as approaches to overcome these in the future.
The Lancet papers serve to shed light on the rigorous process necessary to bring new therapeutics from the bench to the bedside in a successful and timely manner. Human trials will always involve setbacks and challenges, though they often serve to strengthen the end result.
“We wrote these perspectives to explain the challenges we face and adjust some expectations as we aim to find more effective cures for diabetes,” Roep said.
The first paper, “The challenge of modulating β-cell autoimmunity in type 1 diabetes,” was led by Mark Atkinson from the University of Florida College of Medicine and co-authored by Roep.
The second perspective piece, “Antigen-based immune modulation therapy for type 1 diabetes: the era of precision medicine,” was led by Roep and researchers from King's College London.
Between the two papers, Roep says that some revelations were merely wake-up calls. But new facts, such as solid proof that both the disease and patients are heterogeneous, mean that no “magic bullet” therapy can be expected. Not all beta cells are destroyed, as scientists had previously believed, and T1D patients can still have insulin-producing beta cells for decades after diagnosis even if no insulin is secreted. These findings provide new opportunities for further study.
The Road Ahead
“We saw further evidence that T1D is not ‘just’ an autoimmune problem, it is a beta cell problem, where the immune system responds with good intentions to stressed tissue,” Roep said. “This implies that immunotherapy alone will not be enough; we must also treat the beta cells.”
He points to antigen-based therapy as a promising strategy and a positive step away from the classic immune suppression that now is standard therapy in autoimmune diseases and puts patients at risk for cancer and infection. Researchers and physicians need to negotiate with the immune system, rather than bombard it into submission, he added.
“The antigen-based therapies are very exciting and surprising to me,” Roep said. “One could expect that injecting self-made proteins in people with an autoimmune response against these very proteins could aggravate disease. Instead, not only is it safe, this type of therapy serves to re-educate the immune system how to do it right.
“New insight points to new directions, and in revisiting previous immune-intervention trials, you see that there is more success than we appreciated, but usually in minorities of patients,” Roep continued. “Together, these papers show that we are willing and able to tackle the problems in diabetes — whether it’s too strong of an immune response or too few functioning beta cells —from many angles at City of Hope, through the support of the Wanek Project.”
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